MATR3

Summary

MATR3 (matrin 3, HGNC:6912) is a protein-coding gene on chromosome 5q31.2, encoding Matrin-3 (P43243). May play a role in transcription or may interact with other nuclear matrix proteins to form the internal fibrogranular network. It is a selective cancer dependency (DepMap: 14.6% of cell lines).

This gene encodes a nuclear matrix protein, which is proposed to stabilize certain messenger RNA species. Mutations of this gene are associated with distal myopathy 2, which often includes vocal cord and pharyngeal weakness. Alternatively spliced transcript variants, including read-through transcripts composed of the upstream small nucleolar RNA host gene 4 (non-protein coding) and matrin 3 gene sequence, have been identified. Pseudogenes of this gene are located on chromosomes 1 and X.

Source: NCBI Gene 9782 — RefSeq curated summary.

At a glance

• Gene–disease (curated): distal myopathy with vocal cord weakness (Definitive, ClinGen) — +2 more curated relationships
• GWAS associations: 4
• Clinical variants (ClinVar): 622 total — 1 pathogenic
• Phenotypes (HPO): 85
• Druggable target: yes — 1 molecules with ChEMBL bioactivity
• Cancer dependency (DepMap): dependent in 14.6% of screened cell lines
• MANE Select transcript: NM_018834

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:6912
Approved symbol	MATR3
Name	matrin 3
Location	5q31.2
Locus type	gene with protein product
Status	Approved
Aliases	KIAA0723, MGC9105, VCPDM
Ensembl gene	ENSG00000015479
Ensembl biotype	protein_coding
OMIM	164015
Entrez	9782

Gene structure

Transcript identifiers

Ensembl transcripts: 70 — 59 protein_coding, 8 retained_intron, 3 protein_coding_CDS_not_defined

ENST00000361059, ENST00000394800, ENST00000394805, ENST00000502394, ENST00000502422, ENST00000502499, ENST00000502929, ENST00000502944, ENST00000503340, ENST00000503811, ENST00000504023, ENST00000504045, ENST00000504203, ENST00000504311, ENST00000504643, ENST00000505016, ENST00000505625, ENST00000506147, ENST00000507860, ENST00000508689, ENST00000509644, ENST00000509918, ENST00000509990, ENST00000510056, ENST00000511249, ENST00000511333, ENST00000511978, ENST00000512040, ENST00000512107, ENST00000512876, ENST00000513121, ENST00000513678, ENST00000514402, ENST00000514488, ENST00000514528, ENST00000514694, ENST00000515833, ENST00000618441, ENST00000910013, ENST00000910014, ENST00000910015, ENST00000910016, ENST00000910017, ENST00000910018, ENST00000910019, ENST00000910020, ENST00000910021, ENST00000910022, ENST00000910023, ENST00000910024, ENST00000910025, ENST00000910026, ENST00000910027, ENST00000910028, ENST00000910029, ENST00000910030, ENST00000910031, ENST00000928206, ENST00000928207, ENST00000928208, ENST00000928209, ENST00000928210, ENST00000928211, ENST00000955711, ENST00000955712, ENST00000955713, ENST00000955714, ENST00000955715, ENST00000955716, ENST00000955717

RefSeq mRNA: 31 — MANE Select: NM_018834 NM_001194954, NM_001194955, NM_001194956, NM_001282278, NM_001400441, NM_001400442, NM_001400443, NM_001400444, NM_001400445, NM_001400447, NM_001400448, NM_001400450, NM_001400451, NM_001400452, NM_001400453, NM_001400454, NM_001400455, NM_001400456, NM_001400457, NM_001400458, NM_001400459, NM_001400460, NM_001400461, NM_001400462, NM_001400463, NM_001400464, NM_001400465, NM_001400466, NM_001400467, NM_018834, NM_199189

CCDS: CCDS54908, CCDS93789

Canonical transcript exons

ENST00000394805 — 15 exons

Exon	Start	End
ENSE00001407316	139329345	139331677
ENSE00002070863	139293740	139293805
ENSE00003760488	139318908	139319033
ENSE00003761810	139326163	139326284
ENSE00003763930	139322598	139322967
ENSE00003765763	139316076	139316188
ENSE00003766231	139321898	139322029
ENSE00003766301	139315697	139315738
ENSE00003766452	139317053	139317105
ENSE00003766880	139322463	139322506
ENSE00003768957	139319334	139319501
ENSE00003769838	139325440	139325662
ENSE00003771240	139317596	139317721
ENSE00003772093	139307239	139308327
ENSE00003775312	139314675	139314736

Expression profiles

Bgee: expression breadth ubiquitous, 135 present calls, max score 99.64.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 152.1080 / max 2353.9927, expressed in 1823 samples.

FANTOM5 promoters (10 alternative TSS)

Promoter ID	TPM avg	Samples expressed
58814	91.2912	1822
58815	29.4172	1777
58812	16.9571	1785
58813	12.4562	1747
58808	11.0268	1709
58807	0.7331	163
58822	0.3725	151
58817	0.3646	161
203708	0.2666	87
58816	0.2495	90

Top tissues by expression

138 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
cortical plate	UBERON:0005343	99.64	gold quality
corpus callosum	UBERON:0002336	99.62	gold quality
ganglionic eminence	UBERON:0004023	99.58	gold quality
ventricular zone	UBERON:0003053	99.55	gold quality
calcaneal tendon	UBERON:0003701	99.50	gold quality
superior frontal gyrus	UBERON:0002661	99.36	gold quality
endometrium	UBERON:0001295	99.25	gold quality
primary visual cortex	UBERON:0002436	99.15	gold quality
Brodmann (1909) area 9	UBERON:0013540	99.15	gold quality
adrenal tissue	UBERON:0018303	99.11	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	99.09	gold quality
colonic epithelium	UBERON:0000397	99.07	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	99.05	gold quality
prefrontal cortex	UBERON:0000451	99.02	gold quality
smooth muscle tissue	UBERON:0001135	98.92	gold quality
cerebellar hemisphere	UBERON:0002245	98.90	gold quality
cerebellar cortex	UBERON:0002129	98.84	gold quality
tonsil	UBERON:0002372	98.83	gold quality
cerebral cortex	UBERON:0000956	98.81	gold quality
cerebellum	UBERON:0002037	98.81	gold quality
lymph node	UBERON:0000029	98.80	gold quality
nucleus accumbens	UBERON:0001882	98.80	gold quality
ovary	UBERON:0000992	98.73	gold quality
hypothalamus	UBERON:0001898	98.72	gold quality
islet of Langerhans	UBERON:0000006	98.71	gold quality
frontal cortex	UBERON:0001870	98.71	gold quality
left ovary	UBERON:0002119	98.69	gold quality
brain	UBERON:0000955	98.68	gold quality
gall bladder	UBERON:0002110	98.67	gold quality
Ammon’s horn	UBERON:0001954	98.65	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	6.01

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

187 targeting MATR3, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-200B-3P	100.00	73.31	2693
HSA-MIR-200C-3P	100.00	73.35	2685
HSA-MIR-429	100.00	73.44	2698
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-511-3P	99.99	68.85	1467
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-373-5P	99.98	75.36	4753
HSA-MIR-616-5P	99.98	75.58	4775
HSA-MIR-548N	99.98	71.94	4170
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-302C-5P	99.97	72.56	3642
HSA-MIR-548AJ-3P	99.96	73.38	5345
HSA-MIR-548X-3P	99.96	73.38	5345
HSA-MIR-551B-5P	99.96	71.28	3493
HSA-MIR-548AA	99.96	70.64	3753
HSA-MIR-548AP-3P	99.96	70.64	3753
HSA-MIR-548T-3P	99.96	70.64	3753
HSA-MIR-548AB	99.95	71.31	3488
HSA-MIR-559	99.95	72.28	3609
HSA-MIR-9983-3P	99.94	71.48	3631
HSA-MIR-548A-5P	99.94	71.27	3482
HSA-MIR-548AD-5P	99.94	71.23	3502
HSA-MIR-548AE-5P	99.94	71.23	3502
HSA-MIR-548AK	99.94	71.24	3488
HSA-MIR-548AM-5P	99.94	71.24	3488
HSA-MIR-548AP-5P	99.94	71.14	3489

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 14.6% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 40)

• Data show that the nuclear matrix protein matrin 3, cytoskeletal motor protein HMP, and the circadian clock protein lark were significantly decreased in fetal Down syndrome brain. (PMID:12469345)
• These results suggest that the functions of matrin 3 could be regulated by both Ca(2+)-dependent interaction with calmodulin and caspase-mediated cleavage. (PMID:17658460)
• the spatial proximities among a constellation of functionally related sites that are found within euchromatic regions of the cell nucleus including: HP1gamma, RNA polymerase II, matrin 3, and SAF-A sites (PMID:18618731)
• nonconservative S85C missense mutation in vocal cord and pharyngeal weakness with distal myopathy (PMID:19344878)
• study of the association of matr3 with chromosome territories and identification of potential interacting proteins (PMID:19562669)
• MATR3 to be a novel ATM target in response to DNA damage. (PMID:20421735)
• matrin 3 plays a significant role in controlling cell growth and proliferation (PMID:21182838)
• This study identified no pathogenic mutations in BAG3, MATR3, PTRF or TCAP in Australian muscular dystrophy. (PMID:21683594)
• MATR3 binds viral RNA and is required for the Rev/RRE mediated nuclear export of unspliced HIV-1 RNAs. (PMID:21771346)
• Matrin 3 binds Rev RNA to stabilize HIV-1 transcripts leading to increased cytoplasmic expression. (PMID:21771347)
• Rev needs MATR3 to promote the cytoplasmic accumulation and translation of unspliced RRE-containing mRNA. (PMID:21771348)
• Data suggest that the cellular level of MATR3, known to be highly regulated, modulates the stability of a group of gene transcripts. (PMID:21858232)
• the pY RNA1-s2/Matr3 interaction could play a role in vision (PMID:24558381)
• This study identified mutations in MATR3 in ALS kindreds. also observed MATR3 pathology in ALS-affected spinal cords with and without MATR3 mutations. (PMID:24686783)
• Sixteen patients from 6 families with late onset distal myopathy associated with the p.S85C MATR3 mutation were characterized. (PMID:25154462)
• Mutations in MATR3 are rare in French familial ALS and ALS with FTLD patients. (PMID:25158920)
• No mutations were identified, indicating that MATR3 mutations are not a common cause of Amyotrophic lateral sclerosis in Australian familial cases with predominately European ancestry (PMID:25523636)
• MATR3 gene disruption is associated with bicuspid aortic valve, aortic coarctation and patent ductus arteriosus. (PMID:25574029)
• Nuclear matrix protein Matrin3 regulates alternative splicing and forms overlapping regulatory networks with PTB. (PMID:25599992)
• This study shows a high risk of abnormal respiratory function with progressive worsening in MATR3 myopathy. (PMID:25677933)
• MATR3 mutation is identified to be a possible cause of amyotrophic lateral sclerosis. (PMID:25771394)
• Three-dimensional mapping of the lamin A-matrin-3 interface showed that the LMNA truncating mutation Delta303, which lacks the matrin-3 binding domain, was associated with an increased distance between lamin A and matrin-3. (PMID:25948554)
• Suppressing Matrin 3 powers a heightened and broader ZAP restriction of HIV-1 gene expression. (PMID:26129669)
• Its mutations strengthens the role of RNA metabolism in amyotrophic lateral sclerosis etiology. (PMID:26493020)
• Our findings indicate that mutations in Matrin 3 that are associated with ALS and myopathy do not dramatically alter the normal localization of the protein or readily induce inclusion formation. (PMID:26528920)
• It may not be a common genetic factor in Chinese amyotrophic lateral sclerosis patients. (PMID:26708275)
• A missense mutation in MATR3 was identified in myopathy patients undergoing a needle electromyography. (PMID:26899464)
• Depletion of SAFB1 reduced FUS’s localization to chromatin-bound fraction and splicing activity, suggesting SAFB1 could tether FUS to chromatin compartment thorough N-terminal DNA-binding motif. Moreover, FUS interacts with another nuclear matrix-associated protein, Matrin3. (PMID:27731383)
• Using a novel RNA pulldown approach that utilized endogenous S1-tagged PINCR (a p53-regulated long noncoding RNA), the authors show that PINCR associates with the enhancer region of these genes by binding to RNA-binding protein Matrin 3 that, in turn, associates with p53. (PMID:28580901)
• Matrin3 physically interacts with intronic pyrimidine-rich sequences and controls alternative splicing. (PMID:28695676)
• The intra-nuclear localization and interaction network of MATR3 is strongly modulated by its RRM2 domain. (PMID:29511296)
• This might contribute to cellular damage and progression of dystrophy in muscle of Matrin-3 myopathy (PMID:29763601)
• cytoplasmic MATR3 redistribution mitigated neurodegeneration, suggesting that nuclear MATR3 mediates toxicity. (PMID:30015619)
• PTBP1 and MATR3 co-bind and repress RNA processing within and around young LINEs (PMID:30078707)
• FUS, EWSR1, TAF15 and MATR3 within the RNAP II/U1 snRNP machinery play distinct roles in the development of amyotrophic lateral sclerosis and spinal muscular atrophy that are more intimately tied to one another than previously thought. (PMID:30398641)
• In this work we identify the cellular protein MATR3 as an essential cofactor of viral RNA processing. Reactivation of HIV-1 transcription is not sufficient to allow completion of a full life cycle of the virus if MATR3 is depleted. (PMID:30425153)
• identified MATR3 as binding to SNHG1 and the interaction might be involved in splicing events that enhance neuroblastoma progression. (PMID:30516047)
• The data of this study suggest that MATR3 may have regulatory mechanisms that are influenced by tissue type and/or mutation status (PMID:30563574)
• Data shows the expression profile of Gle1, MATR3 and FUS genes in Spinal muscular atrophy (SMA), and suggest a critical role of FUS protein in SMA pathogenesis. Note that the authors appear to erroneously refer to the human MATR3 gene (GeneID: 9782) as MART3 (GeneID: 203430) in this publication. (PMID:30565205)
• MATR3 regulates miR-138 in neurons, with important implications for miR-138 regulation during neuronal development, synaptic plasticity and memory-related processes. (PMID:30790622)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Matr3	ENSMUSG00000037236
rattus_norvegicus	Matr3	ENSRNOG00000019875

Paralogs (1): ZNF638 (ENSG00000075292)

Protein

Protein identifiers

Matrin-3 — P43243 (reviewed: P43243)

All UniProt accessions (21): P43243, A0A0R4J2E8, A0A1B0GX04, A8MXP9, B3KM87, D6R8Z5, D6R991, D6R9F3, D6R9N0, D6RAM9, D6RAY2, D6RB45, D6RBI2, D6RBK5, D6RBS2, D6RCM3, D6RE02, D6REK4, D6REM6, D6RIA2, H0Y8T4

UniProt curated annotations — full annotation on UniProt →

Function. May play a role in transcription or may interact with other nuclear matrix proteins to form the internal fibrogranular network. In association with the SFPQ-NONO heteromer may play a role in nuclear retention of defective RNAs. Plays a role in the regulation of DNA virus-mediated innate immune response by assembling into the HDP-RNP complex, a complex that serves as a platform for IRF3 phosphorylation and subsequent innate immune response activation through the cGAS-STING pathway. Binds to N6-methyladenosine (m6A)-containing mRNAs and contributes to MYC stability by binding to m6A-containing MYC mRNAs. May bind to specific miRNA hairpins.

Subunit / interactions. Part of a complex consisting of SFPQ, NONO and MATR3. Interacts with AGO1 and AGO2. Part of a complex composed at least of ASH2L, EMSY, HCFC1, HSPA8, CCAR2, MATR3, MKI67, RBBP5, TUBB2A, WDR5 and ZNF335; this complex may have a histone H3-specific methyltransferase activity. Interacts with TARDBP. Part of the HDP-RNP complex composed of at least HEXIM1, PRKDC, XRCC5, XRCC6, paraspeckle proteins (SFPQ, NONO, PSPC1, RBM14, and MATR3) and NEAT1 RNA. Interacts with FUS. Interacts with IGF2BP1; the interaction is enhanced by SEPIN14P20 peptide RBPR. Interacts with IGF2BP2 and IGF2BP3. Interacts with RBPMS.

Subcellular location. Nucleus matrix.

Disease relevance. Amyotrophic lateral sclerosis 21 (ALS21) [MIM:606070] A neurodegenerative disorder affecting upper and lower motor neurons, resulting in muscle weakness and respiratory failure. Some patients may develop myopathic features or dementia. The disease is caused by variants affecting the gene represented in this entry.

Isoforms (2)

UniProt ID	Names	Canonical?
P43243-1	1	yes
P43243-2	2

RefSeq proteins (31): NP_001181883, NP_001181884, NP_001181885, NP_001269207, NP_001387370, NP_001387371, NP_001387372, NP_001387373, NP_001387374, NP_001387376, NP_001387377, NP_001387379, NP_001387380, NP_001387381, NP_001387382, NP_001387383, NP_001387384, NP_001387385, NP_001387386, NP_001387387, NP_001387388, NP_001387389, NP_001387390, NP_001387391, NP_001387392, NP_001387393, NP_001387394, NP_001387395, NP_001387396, NP_061322, NP_954659 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000504	RRM_dom	Domain
IPR000690	Matrin/U1-C_Znf_C2H2	Domain
IPR003604	Matrin/U1-like-C_Znf_C2H2	Domain
IPR012677	Nucleotide-bd_a/b_plait_sf	Homologous_superfamily
IPR034928	MATR3_RRM1	Domain
IPR034930	MATR3_RRM2	Domain
IPR035979	RBD_domain_sf	Homologous_superfamily

UniProt features (94 total): modified residue 44, cross-link 18, sequence variant 9, compositionally biased region 7, sequence conflict 5, region of interest 4, domain 2, initiator methionine 1, chain 1, zinc finger region 1, splice variant 1, short sequence motif 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P43243-F1	57.64	0.02

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Post-translational modifications (62): 2, 3, 4, 9, 11, 14, 22, 41, 118, 126, 150, 157, 158, 164, 188, 195, 202, 206, 208, 211 …

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 378 (showing top): GOBP_CARDIAC_CHAMBER_DEVELOPMENT, RODRIGUES_THYROID_CARCINOMA_ANAPLASTIC_UP, GOBP_EMBRYO_DEVELOPMENT_ENDING_IN_BIRTH_OR_EGG_HATCHING, GOBP_CARDIAC_SEPTUM_DEVELOPMENT, RODRIGUES_THYROID_CARCINOMA_POORLY_DIFFERENTIATED_UP, GAUSSMANN_MLL_AF4_FUSION_TARGETS_A_UP, GOBP_BLASTOCYST_FORMATION, GGCNKCCATNK_UNKNOWN, ATGTTAA_MIR302C, GOBP_POSITIVE_REGULATION_OF_RESPONSE_TO_EXTERNAL_STIMULUS, GOBP_POST_TRANSCRIPTIONAL_REGULATION_OF_GENE_EXPRESSION, GOBP_REGULATION_OF_IMMUNE_RESPONSE, SRF_C, GOBP_DEFENSE_RESPONSE_TO_OTHER_ORGANISM, GOBP_IN_UTERO_EMBRYONIC_DEVELOPMENT

GO Biological Process (7): blastocyst formation (GO:0001825), activation of innate immune response (GO:0002218), heart valve development (GO:0003170), ventricular septum development (GO:0003281), post-transcriptional regulation of gene expression (GO:0010608), innate immune response (GO:0045087), immune system process (GO:0002376)

GO Molecular Function (8): RNA binding (GO:0003723), structural molecule activity (GO:0005198), zinc ion binding (GO:0008270), miRNA binding (GO:0035198), identical protein binding (GO:0042802), nucleic acid binding (GO:0003676), protein binding (GO:0005515), metal ion binding (GO:0046872)

GO Cellular Component (4): nucleus (GO:0005634), nuclear inner membrane (GO:0005637), membrane (GO:0016020), nuclear matrix (GO:0016363)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
binding	2
cellular anatomical structure	2
blastocyst development	1
anatomical structure formation involved in morphogenesis	1
activation of immune response	1
positive regulation of innate immune response	1
heart development	1
anatomical structure development	1
cardiac ventricle development	1
cardiac septum development	1
regulation of gene expression	1
immune response	1
defense response to symbiont	1
biological_process	1
nucleic acid binding	1
molecular_function	1
transition metal ion binding	1
regulatory RNA binding	1
protein binding	1
cation binding	1
intracellular membrane-bounded organelle	1
organelle inner membrane	1
nuclear membrane	1
nuclear lumen	1

Protein interactions and networks

STRING

2576 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
MATR3	NONO	P30807	991
MATR3	TARDBP	Q13148	990
MATR3	SFPQ	P23246	954
MATR3	PSPC1	Q8WXF1	921
MATR3	HNRNPC	P07910	900
MATR3	RBM14	Q96PK6	883
MATR3	IGF2BP1	Q9NZI8	875
MATR3	FUS	P35637	874
MATR3	HNRNPM	P52272	871
MATR3	HNRNPA1	P09651	862
MATR3	HNRNPH1	P31943	843
MATR3	SLC23A1	Q9UHI7	841
MATR3	SLC23A2	Q9UGH3	839
MATR3	HNRNPH2	P55795	814
MATR3	DDX5	P17844	803
MATR3	A0A0A6YYI9	A0A0A6YYI9	803

IntAct

309 interactions, top by confidence:

A	B	Type	Score
YWHAB	PIK3C2A	psi-mi:“MI:0914”(association)	0.800
IFIT2	IFIT3	psi-mi:“MI:0914”(association)	0.780
RBM45	HNRNPA1	psi-mi:“MI:0914”(association)	0.740
FUS	MATR3	psi-mi:“MI:0914”(association)	0.730
FUS	MATR3	psi-mi:“MI:0403”(colocalization)	0.730
RASD1	MATR3	psi-mi:“MI:0915”(physical association)	0.720
MATR3	RASD1	psi-mi:“MI:0915”(physical association)	0.720
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
HNRNPK	MATR3	psi-mi:“MI:0915”(physical association)	0.670
MATR3	MATR3	psi-mi:“MI:0915”(physical association)	0.670
MATR3	HNRNPK	psi-mi:“MI:0915”(physical association)	0.670
FUS	HNRNPA1	psi-mi:“MI:0914”(association)	0.670
HTT	MATR3	psi-mi:“MI:0915”(physical association)	0.670
NCBP2	KPNA3	psi-mi:“MI:0914”(association)	0.640
NCBP1	KPNA3	psi-mi:“MI:0914”(association)	0.640
YWHAG	BLTP3B	psi-mi:“MI:0914”(association)	0.640
PAXIP1	KMT2D	psi-mi:“MI:0914”(association)	0.640
RBM45	MATR3	psi-mi:“MI:0915”(physical association)	0.580

BioGRID (919): MATR3 (Two-hybrid), MATR3 (Two-hybrid), RASD1 (Two-hybrid), MATR3 (Affinity Capture-MS), MATR3 (Affinity Capture-MS), MATR3 (Affinity Capture-MS), MATR3 (Biochemical Activity), MATR3 (Affinity Capture-MS), MATR3 (Affinity Capture-MS), MATR3 (Two-hybrid), MATR3 (Affinity Capture-MS), MATR3 (Affinity Capture-MS), MATR3 (Affinity Capture-RNA), MATR3 (Affinity Capture-MS), BTF3 (Co-fractionation)

ESM2 similar proteins: A2RV29, A4QP16, B0JZ85, F4I7L1, O23463, O48772, O64571, P43243, P43244, Q0VD35, Q10KL8, Q28EG9, Q32NW2, Q3KQ71, Q569K4, Q5R4W8, Q5ZDJ6, Q66IH2, Q6AXX3, Q6NPP4, Q6PBT9, Q7XHR2, Q8BXJ8, Q8GSA7, Q8K310, Q8LMR2, Q8S9H7, Q90Y35, Q94AD9, Q9C682, Q9D8C3, Q9ERV1, Q9FFH1, Q9FH37, Q9FYG2, Q9H000, Q9H6B1, Q9H898, Q9LES2, Q9LES3

Diamond homologs: E9PT37, O95758, P0DW16, P17225, P26599, P40567, P43243, P43244, Q00438, Q15233, Q29099, Q3UQS8, Q5FVM4, Q5RFL9, Q5T481, Q66H20, Q6ICX4, Q8BHD7, Q8K310, Q8WN55, Q91Z31, Q99K48, Q9MAC5, Q9UKA9, Q9Z118, Q14966, Q61464, Q9FGL9, Q9ULV3, O74452

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
FUS	“up-regulates activity”	MATR3	relocalization

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 184 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Activation of BAD and translocation to mitochondria	6	37.8×	2e-06
Chk1/Chk2(Cds1) mediated inactivation of Cyclin B:Cdk1 complex	6	33.3×	2e-06
SARS-CoV-1 targets host intracellular signalling and regulatory pathways	6	33.3×	2e-06
Activation of BH3-only proteins	6	24.6×	9e-06
RHO GTPases activate PKNs	6	15.7×	8e-05
Intrinsic Pathway for Apoptosis	6	14.5×	1e-04
SARS-CoV-1-host interactions	9	13.1×	3e-06
Translocation of SLC2A4 (GLUT4) to the plasma membrane	10	12.8×	2e-06

GO biological processes:

GO term	Partners	Fold	FDR
mitophagy	7	13.6×	5e-04
mRNA splicing, via spliceosome	10	5.6×	3e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

622 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	0
Uncertain significance	313
Likely benign	211
Benign	49

Top pathogenic / likely-pathogenic (1)

Variant ID	HGVS	Classification
14002	NM_018834.6(MATR3):c.254C>G (p.Ser85Cys)	Pathogenic

SpliceAI

3294 predictions. Top by Δscore:

Variant	Effect	Δscore
5:139276119:A:AG	acceptor_gain	1.0000
5:139276120:G:GG	acceptor_gain	1.0000
5:139279121:A:G	donor_gain	1.0000
5:139279125:GTAAC:G	donor_gain	1.0000
5:139314737:G:GG	donor_gain	1.0000
5:139314740:G:GT	donor_gain	1.0000
5:139314803:G:GT	donor_gain	1.0000
5:139316059:T:G	acceptor_gain	1.0000
5:139316066:A:AG	acceptor_gain	1.0000
5:139316067:C:G	acceptor_gain	1.0000
5:139316071:ACTAG:A	acceptor_gain	1.0000
5:139316073:TAG:T	acceptor_loss	1.0000
5:139316074:A:AG	acceptor_gain	1.0000
5:139316074:AG:A	acceptor_gain	1.0000
5:139316074:AGG:A	acceptor_gain	1.0000
5:139316075:G:GT	acceptor_gain	1.0000
5:139316075:GG:G	acceptor_gain	1.0000
5:139316075:GGG:G	acceptor_gain	1.0000
5:139316075:GGGGT:G	acceptor_gain	1.0000
5:139316180:G:GT	donor_gain	1.0000
5:139316184:TCTGG:T	donor_gain	1.0000
5:139316186:TGGGT:T	donor_loss	1.0000
5:139316187:GG:G	donor_gain	1.0000
5:139316188:GG:G	donor_gain	1.0000
5:139316188:GGT:G	donor_loss	1.0000
5:139316189:G:GG	donor_gain	1.0000
5:139316189:GT:G	donor_loss	1.0000
5:139316190:T:G	donor_loss	1.0000
5:139317101:GAGTG:G	donor_gain	1.0000
5:139317103:GTG:G	donor_gain	1.0000

AlphaMissense

5627 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
5:139307750:T:C	L112S	1.000
5:139307761:G:C	G116R	1.000
5:139307762:G:A	G116D	1.000
5:139307762:G:T	G116V	1.000
5:139307765:T:A	L117Q	1.000
5:139307765:T:C	L117P	1.000
5:139307777:A:G	D121G	1.000
5:139307777:A:T	D121V	1.000
5:139307789:T:A	L125Q	1.000
5:139307789:T:C	L125P	1.000
5:139307813:T:G	I133S	1.000
5:139307828:T:C	L138S	1.000
5:139307828:T:G	L138W	1.000
5:139307840:T:A	L142H	1.000
5:139307840:T:C	L142P	1.000
5:139307849:T:C	L145P	1.000
5:139308233:C:A	P273H	1.000
5:139308253:G:C	D280H	1.000
5:139308253:G:T	D280Y	1.000
5:139308254:A:C	D280A	1.000
5:139308254:A:G	D280G	1.000
5:139308254:A:T	D280V	1.000
5:139308256:T:C	F281L	1.000
5:139308257:T:C	F281S	1.000
5:139308258:C:A	F281L	1.000
5:139308258:C:G	F281L	1.000
5:139308286:C:G	H291D	1.000
5:139308292:T:A	C293S	1.000
5:139308292:T:C	C293R	1.000
5:139308293:G:A	C293Y	1.000

dbSNP variants (sampled 300 via entrez): RS1000023273 (5:139313389 C>T), RS1000127940 (5:139298082 A>G,T), RS1000141260 (5:139288726 C>T), RS1000173209 (5:139277948 G>A), RS1000178802 (5:139281151 T>C,G), RS1000229804 (5:139304458 C>T), RS1000262140 (5:139290199 A>C,G), RS1000272868 (5:139318339 G>A,C), RS1000297348 (5:139306520 G>A), RS1000389632 (5:139274867 G>A), RS1000432530 (5:139311860 C>A,T), RS1000552576 (5:139330632 T>G), RS1000565161 (5:139276450 A>T), RS1000683449 (5:139281397 C>T), RS1000710667 (5:139283815 C>T)

Disease associations

OMIM: gene MIM:164015 | disease phenotypes: MIM:606070

GenCC curated gene-disease

Disease	Classification	Inheritance
distal myopathy with vocal cord weakness	Definitive	Autosomal dominant
amyotrophic lateral sclerosis type 21	Strong	Autosomal dominant
amyotrophic lateral sclerosis	Supportive	Autosomal dominant

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
distal myopathy with vocal cord weakness	Definitive	AD

Mondo (4): amyotrophic lateral sclerosis type 21 (MONDO:0011632), amyotrophic lateral sclerosis (MONDO:0004976), neurodegenerative disease (MONDO:0005559), distal myopathy with vocal cord weakness (MONDO:0018951)

Orphanet (2): Vocal cord and pharyngeal distal myopathy (Orphanet:600), Amyotrophic lateral sclerosis (Orphanet:803)

HPO phenotypes

85 total (30 of 85 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000217	Xerostomia
HP:0000708	Atypical behavior
HP:0000712	Emotional lability
HP:0000716	Depression
HP:0000726	Dementia
HP:0000739	Anxiety
HP:0000762	Decreased nerve conduction velocity
HP:0001257	Spasticity
HP:0001260	Dysarthria
HP:0001283	Bulbar palsy
HP:0001288	Gait disturbance
HP:0001308	Tongue fasciculations
HP:0001347	Hyperreflexia
HP:0001430	Abnormal calf musculature morphology
HP:0001604	Vocal cord paresis
HP:0001609	Hoarse voice
HP:0001611	Hypernasal speech
HP:0001618	Dysphonia
HP:0001621	Weak voice
HP:0001824	Weight loss
HP:0002015	Dysphagia
HP:0002094	Dyspnea
HP:0002127	Abnormal upper motor neuron morphology
HP:0002145	Frontotemporal dementia
HP:0002180	Neurodegeneration
HP:0002307	Drooling
HP:0002313	Spastic paraparesis
HP:0002317	Unsteady gait
HP:0002360	Sleep disturbance

GWAS associations

4 associations (top):

Study	Trait	p-value
GCST005951_151	Body mass index	6.000000e-07
GCST009391_2121	Metabolite levels	2.000000e-06
GCST010725_68	Malaria	4.000000e-07
GCST010725_7	Malaria	2.000000e-06

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0004340	body mass index
EFO:0010382	phosphatidylcholine 36:4 measurement

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D000690	Amyotrophic Lateral Sclerosis	C10.228.854.139; C10.574.562.250; C10.574.950.050; C10.668.467.250; C18.452.845.800.050
D019636	Neurodegenerative Diseases	C10.574

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL5724643 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

1 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 1,538 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

Molecule	Name	Phase	Patents
CHEMBL1232461	MOLIBRESIB	2	1,538

PharmGKB: 1 entry (VIP=true, CPIC=false)

ChEMBL bioactivities

3 potent at pChembl≥5 of 5 total, top 3 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
7.64	Kd	22.66	nM	CHEMBL5653589
7.64	ED50	22.66	nM	CHEMBL5653589
6.80	IC50	160	nM	MOLIBRESIB

PubChem BioAssay actives

2 with measured affinity, of 10 total; 2 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
4-methyl-3-[(2-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2148724: Binding affinity to human MATR3 incubated for 45 mins by Kinobead based pull down assay	kd	0.0227	uM
2-[(4S)-6-(4-chlorophenyl)-8-methoxy-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-4-yl]-N-ethylacetamide	2178814: Inhibition of MATR3 (unknown origin) incubated for 1 hr by colloidal coomassie staining based LC-MS/MS analysis	ic50	0.1600	uM

CTD chemical–gene interactions

64 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	decreases expression, increases methylation	3
Valproic Acid	decreases expression, increases expression	3
methylmercuric chloride	increases expression	2
trichostatin A	affects cotreatment, decreases expression, affects expression	2
sodium arsenite	decreases expression	2
Air Pollutants	decreases expression, affects cotreatment, increases abundance, increases oxidation	2
Doxorubicin	affects expression, increases expression	2
Cadmium Chloride	decreases expression	2
FR900359	affects phosphorylation	1
bisphenol F	increases expression	1
TAK-243	decreases sumoylation	1
dicrotophos	decreases expression	1
geldanamycin	increases expression	1
alpha-pinene	increases oxidation, increases abundance, affects cotreatment	1
bisphenol A	decreases expression	1
pyrogallol 1,3-dimethyl ether	affects cotreatment, affects localization, increases expression, decreases expression	1
afimoxifene	decreases expression	1
coumarin	decreases phosphorylation	1
methacrylaldehyde	affects cotreatment, increases oxidation, increases abundance	1
beta-methylcholine	affects expression	1
cyclic 3’,5’-uridine monophosphate	affects binding	1
di-n-butylphosphoric acid	affects expression	1
2,3,5-(triglutathion-S-yl)hydroquinone	increases ADP-ribosylation	1
acyline	increases expression	1
entinostat	increases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
nutlin 3	affects cotreatment, increases secretion	1
ICG 001	increases expression	1
dorsomorphin	affects cotreatment, decreases expression	1
jinfukang	decreases expression	1

ChEMBL screening assays

7 unique, capped per target: 7 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5651766	Binding	Binding affinity to human MATR3 incubated for 45 mins by Kinobead based pull down assay	NVP-BHG712: Effects of Regioisomers on the Affinity and Selectivity toward the EPHrin Family. — ChemMedChem

Cellosaurus cell lines

13 cell lines: 10 induced pluripotent stem cell, 3 cancer cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_A4CT	BNIi001-A	Induced pluripotent stem cell	Male
CVCL_A4CU	BNIi001-B	Induced pluripotent stem cell	Male
CVCL_D1HX	HAP1 MATR3 (-) 1	Cancer cell line	Male
CVCL_D1HY	HAP1 MATR3 (-) 2	Cancer cell line	Male
CVCL_D1HZ	HAP1 MATR3 (-) 3	Cancer cell line	Male
CVCL_E4U4	KOLF2.1J MATR3 24.0kbdel DEL/WT	Induced pluripotent stem cell	Male
CVCL_E7LG	KOLF2.1J MATR3 F115C SNV/SNV	Induced pluripotent stem cell	Male
CVCL_E7LH	KOLF2.1J MATR3 F115C SNV/WT	Induced pluripotent stem cell	Male
CVCL_E7LJ	KOLF2.1J MATR3 S85C SNV/SNV	Induced pluripotent stem cell	Male
CVCL_E7LK	KOLF2.1J MATR3 S85C SNV/WT	Induced pluripotent stem cell	Male

Clinical trials (associated diseases)

300 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT00542412	PHASE4	COMPLETED	CARE Canadian ALS Riluzole Evaluation
NCT00560287	PHASE4	UNKNOWN	Non-Invasive Ventilation in Amyotrophic Lateral Sclerosis
NCT00613899	PHASE4	COMPLETED	Feasibility of Telesurveillance and Home Cough Assistance for Amyotrophic Lateral Patients (ALS)
NCT04997954	PHASE4	UNKNOWN	EMERALD TRIAL Open Label Extension Study
NCT06849115	PHASE4	COMPLETED	Effects of L-Carnitine in Amyotrophic Lateral Sclerosis Patients With CHCHD10 Mutations
NCT07223723	PHASE4	RECRUITING	A Study to Learn More About the Long-Term Safety of Tofersen (Qalsody) in Chinese Participants With SOD-1 Amyotrophic Lateral Sclerosis (ALS)
NCT00021697	PHASE3	COMPLETED	Safety/Efficacy of AVP-923 in the Treatment of Emotional Lability (Uncontrolled Crying & Laughing) in Patients With ALS
NCT00035815	PHASE3	COMPLETED	Insulin-like Growth Factor-1 in Amyotrophic Lateral Sclerosis (ALS) Trial
NCT00047723	PHASE3	COMPLETED	Minocycline to Treat Amyotrophic Lateral Sclerosis
NCT00069186	PHASE3	UNKNOWN	Study of Creatine Monohydrate in Patients With Amyotrophic Lateral Sclerosis
NCT00136110	PHASE3	COMPLETED	Trial of Sodium Valproate in Amyotrophic Lateral Sclerosis
NCT00330681	PHASE3	COMPLETED	Efficacy and Safety Study of MCI-186 for Treatment of Amyotrophic Lateral Sclerosis (ALS)
NCT00349622	PHASE3	COMPLETED	Clinical Trial Ceftriaxone in Subjects With ALS
NCT00372879	PHASE3	COMPLETED	Clinical Trial of Vitamin E to Treat Muscular Cramps in Patients With ALS
NCT00415519	PHASE3	COMPLETED	Efficacy and Safety Study of MCI-186 for Treatment of Amyotrophic Lateral Sclerosis (ALS) Who Met Severity Classification III
NCT00424463	PHASE3	COMPLETED	Expanded Controlled Study of Safety and Efficacy of MCI-186 in Patients With Amyotrophic Lateral Sclerosis (ALS)
NCT00839033	PHASE3	TERMINATED	Evaluation of a Mechanical Device During Acute Respiratory Failure in Patients With Neuromuscular Disorders
NCT00868166	PHASE3	COMPLETED	Safety and Efficacy of TRO19622 as add-on Therapy to Riluzole Versus Placebo in Treatment of Patients Suffering From ALS
NCT00965497	PHASE3	COMPLETED	Escitalopram (Lexapro) for Depression MS or ALS
NCT01016522	PHASE3	TERMINATED	Safety and Tolerability of the Ketogenic Diet in Amyotrophic Lateral Sclerosis (ALS)
NCT01160263	PHASE3	COMPLETED	Study of Dopamine and Serotonin Transporters in Patients With Amyotrophic Lateral Sclerosis and Controls
NCT01281189	PHASE3	COMPLETED	Phase 3 Study of Dexpramipexole in ALS
NCT01492686	PHASE3	COMPLETED	Phase 3 Study of MCI-186 for Treatment of Amyotrophic Lateral Sclerosis
NCT01583088	PHASE3	TERMINATED	Early Stage Amyotrophic Lateral Sclerosis Phrenic Stimulation
NCT01622088	PHASE3	TERMINATED	Phase 3 Extension Study of Dexpramipexole in ALS
NCT02496767	PHASE3	COMPLETED	Ventilatory Investigation of Tirasemtiv and Assessment of Longitudinal Indices After Treatment for a Year
NCT02623699	PHASE3	COMPLETED	An Efficacy, Safety, Tolerability, Pharmacokinetics and Pharmacodynamics Study of BIIB067 (Tofersen) in Adults With Inherited Amyotrophic Lateral Sclerosis (ALS)
NCT02936635	PHASE3	COMPLETED	A Study for Patients Who Completed VITALITY-ALS (CY 4031)
NCT03127267	PHASE3	RECRUITING	Efficacy and Safety of Masitinib Versus Placebo in the Treatment of ALS Patients
NCT03280056	PHASE3	COMPLETED	Safety and Efficacy of Repeated Administrations of NurOwn® in ALS Patients
NCT03491462	PHASE3	COMPLETED	Arimoclomol in Amyotropic Lateral Sclerosis
NCT03505021	PHASE3	COMPLETED	Effects of Oral Levosimendan (ODM-109) on Respiratory Function in Patients With ALS
NCT03548311	PHASE3	COMPLETED	Clinical Trial of Ultra-high Dose Methylcobalamin for ALS
NCT03690791	PHASE3	UNKNOWN	Efficacy of Cannabinoids in Amyotrophic Lateral Sclerosis or Motor Neurone Disease
NCT03800524	PHASE3	UNKNOWN	Safety and Efficacy of TUDCA as add-on Treatment in Patients Affected by ALS
NCT03836716	PHASE3	TERMINATED	Arimoclomol in Amyotropic Lateral Sclerosis - Open Label Extension Trial
NCT03948178	PHASE3	TERMINATED	Effects of Oral Levosimendan on Respiratory Function in Patients With Amyotrophic Lateral Sclerosis (ALS): Open-Label Extension
NCT04165824	PHASE3	COMPLETED	Safety Study of Oral Edaravone Administered in Subjects With ALS
NCT04248465	PHASE3	TERMINATED	An Efficacy and Safety Study of Ravulizumab in ALS Participants
NCT04569084	PHASE3	TERMINATED	Efficacy and Safety Study of Oral Edaravone Administered in Subjects With ALS